The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for cancer imaging and therapy. It is an important prognostic marker in the case of prostate cancer (PCa), where its expression portends an earlier biochemical relapse. Imaging PSMA in experimental models of PCa has been used to report on androgen signaling and response to taxane therapy. New PSMA- targeted therapies are appearing in the clinic. For example, Progenics Pharmaceuticals, Inc. has a PSMA- targeted antibody-drug conjugate that demonstrated efficacy in its phase I trial, leading to a phase II tria. Treatment with docetaxel-impregnated, PSMA-targeted poly(lactic-co-glycolic acid) nanoparticles caused regression of lung lesions in patients with metastatic cholangiocarcinoma. Concurrently a wide variety of imaging agents for PSMA is beginning to circulate. In the past year year the first three clinical papers that employ low molecular weight agents for imaging PSMA have appeared. The first such agent, [18F]DCFBC, developed by us, is coming online within the Molecular Imaging Program at the National Cancer Institute. We intend to use a pharmacokinetically optimized second generation compound, [18F]DCFPyL, as the second of several PSMA-targeted imaging agents for positron emission tomography (PET) that we are developing and will transfer to NCI to be validated in patients with metastatic, castrate-resistant PCa (CRPC). We will also use this agent to check for intra-prostatic lesions for validation in that setting as well as in the setting of treatment with anti-androgen therapy and eventual biochemical recurrence. The overall goal is to validate [18F]DCFPyL clinically so that it can be used to full advantage in supporting existing and emerging therapies for a spectrum of patients suffering from PCa. We will also correlate imaging findings with potentially altered signaling pathways in PCa derived from biopsy specimens. That will occur across four Specific Aims: (1) performance comparison of [18F]DCFPyL to [18F]DCFBC through a first-in-human study of the former to decide with which to move forward in subsequent aims; (2) To image treatment-naive patients with localized-locally advanced primary PCa using DCFPyL-PET/magnetic resonance imaging (hypothesizing superior performance of the second generation compound), and correlate signal with that on MR concurrently obtained, as well as with tumor grade, PSMA expression and androgen receptor (AR) signaling before and after two months of neoadjuvant androgen deprivation (ADT); (3) To image patients with CRPC using DCFPyL- PET/MR and correlate findings with bone and soft tissue biopsy; (4) To image patients with CRPC with DCFPyL-PET/MR and correlate with standard 99mTc-based bone scan to guide stereotactic body radiation treatment (SBRT) in patients with oligometastatic disease. This project will be a new, transdisciplinary collaboration between molecular imaging researchers and medical and radiation oncologists at Johns Hopkins University, the NCI Molecular Imaging Program and the NIH Clinical Center.